Cyclopentane derivatives

ABSTRACT

1. A CYCLOPENTANE OF THE FORMULA:   A&lt;(-CH(-(CH2)2-CH(-O-R3)-R1)-CH(-(CH2)M-CO-R3)-(CH2)2-)   WHEREIN A IS CARBONYL OR -CH(OR3)-, R1 IS ALKYL OF 1 THROUGH 10 CARBON ATOMS, CYCLOALKYL OF 3 TO 10 CARBON ATOMS, OR ALKYL OR 1 THROUGH 4 CARBON ATOMS SUBSTITUTED BY CYCLOALKYL OF 3 THROUGH 10 CARBON ATOMS, M IS 4 OR 6, R2 IS HYDROXYL OR -OR4, WHEREIN R4 IS ALKYL OR 1 THROUGH 4 CARBON ATOMS, AND R3 IS HYDROGEN, ALKYL OF 1 THROUGH 4 CARBON ATOMS, OR ALKANOYL OF FORMULA   -CO-R9 WHEREIN R9 IS ALKYL OF 1 THROUGH 4 CARBON ATOMS, AND, WHEN A IS -CH(OR3)-, THE SYMBOLS R3 ARE THE AME, AND, WHEN R2 IS HYDROXY, PHARMACEUTICALLY ACCEPTABLE NONTOCXIC SALTS THEREOF.

United States Patent 3,845,096 CYCLOPENTANE DERIVATIVES Michael PeterLear Caton, Upminster, Arevor Parker, Fomford, and Gordon LeonardWatkins, Dagenham, England, assignors to May & Baker Limited, Essex,England No Drawing. Original application May 26, 1971, Ser. No. 147,273,now Patent No. 3,751,463. Divided and this application Nov. 7, 1972,Ser. No. 304,467

Claims priority, application Great Britain, May 27, 1970,

70 Int. Cl. C07c 61/36, 61/37, 69/74 US. Cl. 260-468 D 15 ClaimsABSTRACT OF THE DISCLOSURE Compounds of the formula:

I (CH1) ..-o o R2 Q RI This is a division of application Serial No.147,273 filed May 26, 1971, now patent No. 3,751,463.

This invention relates to new cyclopentane derivatives, processes fortheir preparation, and compositions containing them.

According to the present invention there are provided the newcyclopentane derivatives of the general formula:

germs-13 0 R2 E) R I (wherein A represents a carbonyl group or a groupof the general formula:

R represents an alkyl group containing from 1 to (preferably 5) carbonatoms, a cycloalkyl group, or an alkyl group substituted by a cycloalkylgroup, m represents 4 or 6, R represents a hydroxy group or a group ofthe general formula III, IV or, except where A represents a carbonylgroup, V:

--O R N -NHN III IV V wherein R represents an alkyl group, R R R" and Reach represent a hydrogen atom or an alkyl group, and R represents ahydrogen atom, an alkyl group or, except where R represents a group offormula IV or V, a group of the general formula:

wherein R represents an alkyl group; when A represents a group offormula II the symbols R represent identical groups) and, when Rrepresents a hydroxy group, nontoxic salts thereof. In thisSpecification it is to be understood that, unless otherwise specified,alkyl groups contain from 1 to 4 carbon atoms and cycloalkyl groupscontain from 3 to 10 carbon atoms.

The compounds of general formula I and their nontoxic salts possessvaulable pharmacodynamic properties, in particular hypotensive activityand reduction in gastric acid secretion. For example, in laboratoryscreening methods the compounds produce a 10 mm. Hg fall in the meanblood pressure of the urethaneanaesthetized, pempidine-treated rat atdoses between 0.1 and 3.0 mg./ kg. animal body weight administeredintravenously, while doses between 0.05 and 2.0 mg./kg. animal bodyweight administered orally produce a 50% reduction in the gastric acidsecretion induced in the rat by continuous intravenous infusion ofpentagastrin.

According to a feature of the present invention, the compounds ofgeneral formula I, wherein R represents a hydroxy group and R representsa hydrogen atom or an alkyl group, are prepared by the alkalinehydrolysis of compounds of formula I wherein R represents a group offormula III. Hydrolysis is preferably effected by treatment with analkali metal hydroxide, e.g. sodium hydroxide, in an aqueous-organicsolvent, e.g. aqueous ethanol, if desired at an elevated temperature,for example 40- C., e.g. the reflux temperature of the reaction mixture.

Compounds of general formula I, wherein A represents a group of formulaII, R represents a group of formula III and the symbols R representhydrogen atoms, are prepared by the acid hydrolysis of compounds of thegeneral formula:

VII

VIII

wherein R R and R are as hereinbefore defined, and n represents 1 or 2.Reduction is preferably effected by bydrogenation in the presence of ahydrogenation catalyst, for example palladium on charcoal, in thepresence of an inert organic solvent, for example a lower alkanol, e.g.ethanol, at laboratory temperature and elevated pressure, e.g. at ahydrogen pressure of 15 kilograms per square centimetre.

Compounds of general formula VIII may be prepared by the reaction ofcompounds of the general formula:

-CHO

6R" R 1X (wherein R and R are hereinbefore defined) with compounds ofthe general formula:

H (R -P=C =CCOOR (wherein R R and n are as hereinbefore defined, and Xrepresents a bromine or chlorine atom) with an inorganic base, forexample an alkali metal hydroxide, e.g. sodium hydroxide, in water, at atemperature between 0 C. and C., preferably between 0 C. and 4 C.

Compounds of general formula XI may be prepared by the reaction ofcompounds of the general formula:

(R )a XII (wherein R is as hereinbefore defined) with a compound of thegeneral formula:

\ n XIII (wherein R 11 and X are as hereinbefore defined) in a dry inertorganic solvent, for example an aromatic hydrocarbon, e.g. benzene.

Compounds of general formula XII'I may be prepared by the methodsdescribed by Ziegler, Spath, Schaaf, Schumann and Winkelmann, Annalen,551, (1942), 80, and Heilbron, Jones and OSullivan, J.C.S., (1946), 866.

Compounds of general formula IX may be prepared by the reduction ofcompounds of the general formula:

2 3 011 OR" XIV (wherein R and R are as hereinbefore defined) by meansof a known complex metal reducing agent, preferably a dialkylaluminumhydride (e.g. di-isobutylaluminum hydride), in a dry inert organicsolvent, for example an aromatic hydrocarbon (e.g. benzene) or an ether(e.g. diethyl ether), at temperatures between -80 C. and +30 C.

Compounds of general formula XIV may be prepared by the reaction ofcompounds of the general formula:

(wherein R is as hereinbefore defined) with two molar proportions of2,3-dihydropyran or the appropriate alkylated 2,3-dihydropyran per molarproportion of compound of formula XV in the presence of a catalyticamount of an acid, for example a mineral acid, e.g. concentratedhydrochloric acid. Reaction is preferably effected in the presence of aninert organic solvent, for example a halogenated hydrocarbon, e.g.dichloromethane, at laboratory temperature or with heating, for exampleto temperatures between 40 C. and 60 C.

Compounds of general formula XV may be prepared by the simultaneousdeacetylation and reduction of compounds of the general formula:

E 0 000cm XVI wherein R is as hereinbefore defined. The reaction ispreferably effected by treatment of compounds of formula XVI with analkali metal borohydride, for example sodium borohydride, in thepresence of an aqueous alkali metal hydroxide, for example sodiumhydroxide, and, if desired, an inert organic solvent, for example alower alkanol, e.g. methanol, at an elevated temperature, preferably atemperature of 50 to 60 C.

Compounds of general formula XVI may be prepared by the reaction ofcompounds of the general formula:

0 C O XVIII (wherein R is as hereinbefore defined) with a halogen,preferably bromine, in an inert organic solvent, for example ahalogenated hydrocarbon (e.g. carbon tetrachloride), preferably at atemperature between 0 and 10 C., followed by treatment with a base, forexample (a) a tertiary amine, e.g. triethylamine, preferably in thepresence of an inert organic solvent, for example a halogenatedhydrocarbon (e.g. carbon tetrachloride), and at an elevated temperature,advantageously at the reflux temperature of the reaction mixture, or (b)an aqueous inorganic base, for example an alkali metal carbonate, e.g.sodium carbonate, preferably at room temperature.

Compounds of general formula XVIII may be prepared by the reaction ofcompounds of the general formula:

XIX

(wherein R is as hereinbefore defined) with an acetylating agent,preferably a lower alkenyl acetate, for example isopropenyl acetate.

The reaction is preferably carried out in the presence of an organicacid, for example p-toluenesulphonic acid, using an excess of the loweralkenyl acetate as a solvent, at an elevated temperature so as tomaintain continuous removal of the alkanone formed during the reaction.

Compounds of general formula XIX may be prepared by aqueous acidhydrolysis of compounds of the general formula OR OR OCOCH; XX

OR OR12 5H XXI (wherein R and R are as hereinbefore defined) with anacetylating agent, for example acetic anhydride, preferably at anelevated temperature, e.g. at temperatures up to 100 C.

Compounds of general formula XXI may be prepared by the reduction ofcompounds of the general formula:

O R" 0 IR XXII wherein R and R are as hereinbefore defined. Reduc tionis preferably effected by hydrogenation in the presence ofahydrogenation catalyst, e.g. Raney nickel, in the presence of an inertorganic solvent, for example a lower alkanol, e.g. ethanol, preferablyat elevated temperature and pressure, for example at 105 C. and ahydrogen pressure of 45 kilograms per square centimetre, or by treatmentwith a complex metal reducing agent, for example an alkali metalborohydride (e.g. sodium borohydride), in an aqueous organic solvent,for example an aqueous lower alkanol, e.g. ethanol, at temperatures between, for example, 0 C. and room temperature.

Compounds of general formula XXII may be prepared by the reaction ofcompounds of the general formula:

0 iz 0 12 XXIII (wherein R is as hereinbefore defined) with a Grignardreagent represented by the general formula:

R Mg X XXIV (wherein R is as hereinbefore defined, and X represents ahalogen, preferably bromine, atom), or with a metal alkyl, wherein thealkyl moiety corresponds to the group R for example an alkyl lithium, inan inert organic solvent, for example a lower dialkyl ether, e.g. diethyether. Reaction is preferably effected at an elevated temperature, forexample, the reflux temperature of the reaction mixture.

Compounds of general formula XXIII may be prepared by the application oradaptation of known methods, for example as described by T. Henshall andE. W. Parnell, J. C. S. (1962), 661.

6 Compounds of general formula XXI may alternatively be prepared by thereaction of compounds of the general formula:

CHO

OR" OR" XXV (wherein R is as hereinbefore defined) with a Grignardreagent of formula XXIV or a metal alkyl, wherein the alkyl moietycorresponds to the group R for example an alkyl lithium, in an inertorganic solvent, for example a lower dialkyl ether, e.g. diethyl ether.Reaction is preferably effected at an elevated temperature, for examplethe reflux temperature of the reaction mixture.

Compounds of general formula XXV may be prepared by the reduction ofcompounds of formula XXIII by means of a known complex metal reducingagent, preferably a dialkylaluminium hydride (e.g. di-isobutylaluminiumhydride), in a dry inert organic solvent, for example an aromatichydrocarbon (e.g. benzene) or an ether (e.g. diethyl ether) attemperatures between C. and +30" 0.

Compounds of general formula I wherein A represents a group of formulaII, R represents a group of formula III and the symbols R representhydrogen atoms, may alternatively be prepared by the reduction of thedouble bonds of compounds of the general formula:

nmi

' I (wherein R is as hereinbefore defined) with compounds of formula X,preferably under the same conditions as hereinbefore mentioned inrespect of the reaction between compounds of formulae IX and X.

Compounds of general formula XXVII may be prepared by the reaction ofcompounds of formula XVI with a known complex metal reducing agentsuitable for the simultaneous reduction of the ketone and acetoxy groupsto hydroxy groups, and the cyano group to a carbaldehyde group withoutaffecting the rest of the molecule, preferably a dialkyl-aluminiumhydride, for example di-isobutyl aluminium hydride, at temperaturesbetween 80 C. and +30 C. Preferably the reaction is effected in thepresence of a dry insert organic solvent, for example an ether (e.g.diethyl ether) or an aromatic hydrocarbon (e.g. benzene).

Compounds of general formula I wherein A represents a carbonyl group, Rrepresents a hydroxy group and R represents a hydrogen atom, areprepared.

(a) by the acid hydrolysis of compounds of the general formula:

-(CH2)mCOOH wherein R R and m are as hereinbefore defined. Hydrolysis ispreferably effected under mildly acidic conditions, for example at roomtemperature using an 80% aqueous acetic acid solution.

Compounds of general formula XXVIII may be prepared by the alkalinehydrolysis of compounds of the general formula:

wherein R R R and m are as hereinbefore defined. Hydrolysis ispreferably elfected by treatment with an alkali metal hydroxide, e.g.sodium hydroxide, in an aqueous-organic solvent, e.g. aqueous ethanol,if desired at an elevated temperature, e.g. the reflux temperature ofthe reaction mixture or (b) from compounds of formula XXIX by theconversion of the groups =C(OR and -COOR to carbonyl and carboxy groupsrespectively in the reverse order, by acid hydrolysis followed byalkaline hydrolysis, under conditions like to those hereinbeforedescribed for the said hydrolyses in process (a).

Compounds of general formula XXIX may be prepared by the reduction ofthe double bonds of compounds of the general formula:

WOOCR I O R O R H XXXI (wherein R and R are as hereinbefore defined)with compounds of formula X, preferably under the same conditions ashereinbefore mentioned in respect of the reaction between compounds offormulae IX and X.

Compounds of general formula XXXI may be prepared by the reduction ofcompounds of the general formula:

O CO CH; XXXII (wherein R and R are as hereinbefore defined) by means ofa complex metal reducing agent known for conversion of the acetoxy groupto a hydroxy group and the cyano group to a carbaldehyde group,preferably a dialkyl-aluminum hydride (e.g. di-isobutylaluminumhydride), in an inert organic solvent, for example an aromatichydrocarbon (e.g. benzene) or an ether (e.g. diethyl ether), attemperatures between -80 C. and +30 C.

Compounds of general formula XXXII may be prepared from compounds offormula XVI by known meth ods for the preparation of ketals fromketones, for example by the reaction of a compound of formula XVI withthe appropriate alcohol or diol with an acidic catalyst, for examplep-toluenesulphonic acid, with continuous removal of water.Advantageously the reaction is effected in the presence of an inertorganic solvent, for example an aromatic hydrocarbon (e.g. benzene), atan elevated temperature, such that the continuous removal of water iscarried out by the use of a Dean and Stark apparatus.

Many compounds of general formula I can also be prepared from othercompounds of formula I, as will be readily appreciated by those skilledin the art, for example:

Compounds of general formula I, wherein R represents a group of formulaIII and R represents an alkyl group, can be prepared by reaction ofcompounds of formula I wherein R represents a group of formula III and Rrepresents a hydrogen atom with:

(a) Compounds of the general formula:

R Y XXXIII (wherein R represents an alkyl group, and Y represents theacid residue of a reactive ester, e.g. a bromine, chlorine or iodineatom or a sulphonate or sulphate group), optionally in the presence ofan inert organic solvent, for example an aromatic hydrocarbon (e.g.benzene), in the presence of an alkali metal, an alkali metal hydride,for example sodium hydride, or a suitable metal oxide, preferably silveroxide, preferably at a temperature of 50-150" C.

(b) (Where R may be represented by the formula --CHR R wherein R and R,which may be the same or different, represent hydrogen atoms or alkylgroups containing from 1 to 3 carbon atoms, such that the group Rcontains a maximum of 4 carbon atoms) compounds of the general formula:

R XXXI V (wherein R and R are as hereinbefore defined), in the presenceof a suitable Lewis acid, for example boron trifluoride, in an inertorganic solvent, preferably a dialkyl ether (e.g. diethyl ether) at atemperature between 40 C. and +20 C., preferably between 40 C. and 10 C.

Compounds of general formula I, wherein R represents a hydroxy group ora group of formula III and R represents a group of formula VI, can beprepared by the reaction of compounds of formula I, wherein R representsa hydroxy group or a group of formula III, and R represents a hydrogenatom, with compounds of the general formula:

(wherein R is as hereinbefore defined), preferably at ambienttemperature and preferably in the presence of a base, for example,pyridine. The reaction may be effected in the presence of an inertorganic solvent, for example an aromatic hydrocarbon (e.g. benzene).

Compounds of general formula I, wherein R represents a group of formulaIV or V and R represents a hydrogen atom or an alkyl group, can beprepared by the reaction of compounds of formula I, wherein R representsa group of formula III and R represents a hydrogen atom or an alkylgroup, with a compound of formula XXXVI or XXXVII:

XXXV

(wherein R R, R and R are as hereinbefore defined), in an inert organicsolvent, e.g. a lower alkanol (preferably ethanol), preferably atelevated temperatures, for example 50 to C., and advantageously at thereflux temperature of the reaction mixture, optionally in the presenceof a basic catalyst, for example an alkali metal alkoxide in a loweralkanol, e.g. sodium ethoxide in ethanol.

Alternatively, compounds of general formula I wherein R represents agroup of formula IV or V and R represents an alkyl group can be preparedby the reaction of an acid halide of the general formula:

gormmoo z Q/ XXXVIII (wherein A, m and R are as hereinbefore defined, Rrepresents an alkyl group and Z represents a halogen atom, preferably achlorine atom) with a compound of formula XXXVI or XXXVII, optionally inan inert organic solvent, for example a dialkyl ether (e.g. diethylether), preferably at ambient temperature.

Compounds of general formula XXXVIII may be prepared from the parentacids by known methods for the preparation of acid halides, for example,where Z represents a chlorine atom, by the reaction with an excess ofthionyl chloride optionally in an inert organic solvent (e.g. benzene)and preferably at ambient temperature.

Compounds of general formula I wherein R represents a group of formulaIII and R represents a hydrogen atom or an alkyl group can be preparedby the reaction of compounds of formula I wherein R represents a hydroxygroup and R represents a hydrogen atom or an alkyl group with:

(a) Compounds of the general formula:

(wherein R is as hereinbefore defined), an excess of which may beemployed as solvent medium, in the presence of an aqueous inorganicacid, for example hydrochloric acid or sulphuric acid, preferably attemperatures between 50 C. and 110 C., and advantageously at the refluxtemperature of the reaction mixture.

(b) [Where R may be represented by the formula -CHR R (wherein R and Rare as hereinbefore defined)] compounds of formula XXXIV, in an inertorganic solvent, preferably a dialkyl ether (e.g. diethyl ether),preferably at ambient temperature.

(c) Silver oxide or other reagents known in the art for the productionof silver salts of carboxylic acids, followed by reaction of the silversalts so formed with compounds of the general formula:

(wherein R and Y are as hereinbefore defined), optionally in thepresence of an inert organic solvent, for example, an aromatichydrocarbon (e.g. benzene) at an elevated temperature and advantageouslyat the reflux temperature of the reaction mixture.

. By the term non-toxic salts, as used in the present specification, ismeant salts the cations of which are relatively innocuous to the animalorganisms when used in therapeutic doses so that the beneficialpharmacological properties of the parent acid compound of generalformula I are not vitiated =by side-effects ascribable to those cations.Preferably the salts are water-soluble. Suitable salts include thealkali metal, e.g. sodium and potassium, and ammonium salts andpharmaceutically-acceptable (i.e. non-toxic) amine salts.

Amines suitable for forming such salts with carboxylic acids are wellknown and include, for example, amines derived in theory by thereplacement of one or more of the hydrogen atoms of ammonia by groups,which may be the same or different when more than one hydrogen atom isreplaced, selected from alkyl groups containing from 1 to 6 carbonatoms, hydroxyalkyl groups containing from 1 to 3 carbon atoms,cycloalkyl groups containing from 3 to 6 carbon atoms, phenyl groups,phenylalkyl groups containing from 7 to 11 carbon atoms and phenylalkylgroups containing from 7 to 15 carbon atoms wherein the alkyl moietiesare substituted by hydroxy groups. The phenyl group and phenyl moietiesof such phenylalkyl groups may be unsubstituted or substituted by one ortwo alkyl groups containing from 1 to 6 carbon atoms. Suitable aminesalso include those derived in theory by the replacement of two of thehydrogen atoms of ammonia by a hydrocarbon chain, which may beinterrupted by nitrogen, oxygen or sulphur atoms, to form, together withthe nitrogen atom of ammonia to which its terminal groups are attached,a fiveor six-membered nitrogen containin heterocyclic ring, whichheterocyclic ring may be unsubstituted or substituted by one or twoalkyl groups containing from 1 to 6 carbon atoms. Examples of suitableamine cations include mono-, diand tri-methylammonium, mono-, diandtri-ethylammonium, mono-, diand tri-propylammonium, mono-, diandtri-isopropylamonium, ethyldimethylammonium, mono-, diand tri-2-hydroxyethylammonium, ethylbis(2 hydroxyethyl)ammonium, butylmono(2hydroxyethyl)ammonium, tris (hydroxymethyl)methylammonium,cyclohexylammo nium, benzylammonium, benzyldimethylammonium,dibenzylammonium, phenyl 2 hydroxyethylammonium, piperidinium,morpholinium, pyrrolidinium, piperazinium, l-methylpiperidinium,4-ethylmorpholinium, l-isopropylpyrrolidinium, 1,4-dimethylpiperazinium,l-butylpiperidinium, 2-methylpiperidinium andl-ethyl-Z-methylpiperidinium.

The non-toxic salts may be prepared from parent compounds of formula Iby known methods, for example by reaction of stoichiometric quantitiesof compounds of formula I (wherein R represents a hydroxy group) and theappropriate base, e.g. an alkali metal hydroxide or carbonate, ammoniumhydroxide, ammonia or an amine, in a suitable solvent which ispreferably water in the case of the preparation of alkali metal saltsand water or isopropanol in the case of amine salts. The salts may beisolated by lyophilisation of the solution or, if sufiiciently insolublein the reaction medium, by filtration, if necessary after removal ofpart of the solvent.

By the term known methods as used in the present Specification is meantmethods heretofore used or described in the chemical literature.

Preferred compounds of general formula I according to the presentinvention are those in which R represents and n-pentyl group, mrepresents 6, R represents a hydroxy group, a group of formula IIIwherein R represents a methyl or ethyl group (i.e. a methoxy or ethoxygroup), a group of formula IV wherein R represents a hydrogen atom and Rrepresents a methyl group (i.e. methylamino), or a group of formula Vwherein R and R both represent hydrogen atoms (i.e. hydrazine), and Rrepresents a hydrogen atom, a methyl group, or a group of formula VIwherein R represents a methyl group (i.e. acetyl) and, where Rrepresents a hydroxy group, nontoxic salts thereof. Especially preferredis the stereoisomer of7-[3-hydroxy-2-(3-hydroxyoctyl)cyclopentylJheptanoic acid where therelative configuration of the hydroxy group on the cyclopentane ring isthought to be trans to the 3-hydroxyoctyl side chain, which has thefollowing spectroscopic properties:

11 1700 CHM-'1 (liquid film), N.M.R. (approximately 10% solution indeuterochloroform) 0.896 (triplet J=4 V2 c./s., terminal CH3), 1.386(singlet, chain CH 1.4-6 (multiplets), 2.326 (triplet J'=5 /2 c./s., CHCO), 3.58 and 3.855 (multiplets), 5.56 (3H=OH and COOI-I): and mixturesof this compound with its cis-isomer.

The following Examples illustrate the preparation of new compounds ofthe present invention.

EXAMPLE 1 (a) Preparation of 1,4-dioxa-6-(3oxooctyl)spiro- [4,4]nonane Asolution of 1,4 dioxa 6 (2-cyanoethyl)spir0 [4,4] nonane [prepared bythe method described by T. Hensall and E. W. Parnell, J. C. S. (1962),661] (372 g.) in dry diethyl ether (1 litre) was added dropwise withstirring over 0.75 hours to pentyl magnesium bromide [1.5 equivalents,prepared by adding pentyl bromide (491 g.) in dry diethyl ether (750ml.) to magnesium (90.6 g.) in dry diethyl ether (1.5 litres)]. Themixture was then refluxed for 2 hours and the cooled reaction mixturedecomposed by careful addition of a saturated aqueous ammonium chloridesolution, filtered, and the ether phase separated. The aqueous phase wasextracted twice more with diethyl ether and the combined ether extractsdried over anhydrous magnesium sulphate. The diethyl ether was removedin vacuo and the residue distilled to give crude 1,4-dioxa-6-(3oxooctyl)spiro[4,4]nonane, b.p. 110-145 C./0.1 mm. Hg. This wasredistilled to give 1,4-dioxa-6-(3-oxooctyl)spiro[4,4]nonane (251 g.),b.p. 135-140 C./0.050.1 mm. Hg; n =1.462.

(b) Preparation of 1,4-dioxa-6-(3-hydroxyoctyl) spiro[4,4]nonane1,4-Dioxa-6-(3 oxooctyl)spiro[4,4]nonane (250 g.) [prepared as describedin (a) above] in ethanol (100 ml.) was catalytically hydrogenated usingRaney nickel (37.5 g., hydrogen pressure 45 kg./cm. at 105 C. for 8hours. After removal of the catalyst by filtration and evaporation ofthe ethanol in vacuo, the residue gave 1,4-dioxa-6-(3-hydroxyoctyl)spiro[4,4]nonane (230 g.), b.p. 120130C./0.1-0.05 mm. Hg; n =1.4715.

(c) Preparation of 1,4-dioxa-6-(3-acetoxyoctyl) spiro [4,4] nonane1,4-Dioxa-6-(3 hydroxyoctyl)spiro[4,4]nonane (229 g.) [prepared asdescribed in (b) above] in acetic anhydride (1150 ml.) was heated at 100C. for 2 hours. The excess acetic anhydride was removed in vacuo and theresidue distilled to give 1,4-dioxa-6-(3-acetoxyoctyl) spiro[4,4]nonane(245 g.), b.p. 140145 C./0.05 mm. Hg; n =1.458.

(d) Preparation of 2-(3-acetoxyoctyl)cyclopentanone 1,4-Dioxa-6-(3acetoxyoctyl)spiro[4,4]nonane (244 g.) [prepared as described in (c)above], glacial acetic acid (960 ml.) and water (240 ml.) were allowedto stand at room temperature for 3 days with occasional shaking. Themixture was diluted with water (6 1.) extracted with diethyl ether andthe ether extracts washed with water, saturated aqueous sodiumbicarbonate, water and saturated aqueous sodium chloride solution. Afterdrying over anhydrous magnesium sulphate and evaporation of the other invacuo, the residue was distilled to give2-(3-acetoxyoctyl)cyclopentanone (179 g.), b.p. 120- 125 C./0.07 mm. Hg;n =1.456.

(e) Preparation of 1-acetoxy-2-(3-acetoxyoctyl) cyclopent-l-ene2-(3-Acetoxyoctyl)cyclopentanone (85 g.) [prepared as described in (d)above], isopropenyl acetate (125 m1.) and p-toluenesulphonic acid (2 g.)were refluxed for 24 hours allowing the acetone formed during thereaction to slowly distil from the head of a Dufton column. The excessisopropenyl acetate was then distilled oif and the residue cooled,shaken with 2N sodium carbonate solution and extracted with diethylether. The combined ether extracts were dried over anhydrous magnesiumsulphate and the ether removed in vacuO. Distillation of the residuegave l-acetoxy-Z-(3-acetoxyoctyl)cyclopent-l-ene (85 g.) b.p. 108110C./0.03 mm. Hg; n =1.459.

(f) Preparation of 2-(3-acetoxyoctyl)cyclopent-Z-enone To a stirredsolution of 1-acetoxy-2-(3-acetoxyoctyl) cyclopent-l-ene (59.2 g.)[prepared as described in (e) above] in dry carbon tetrachloride (350ml.) was added dropwise, during 30 minutes, a solution of bromine (32g.) in dry carbon tetrachloride (100 ml.) at 10 to C. The solution wasstirred for a further 20 minutes without cooling. Triethylamine (22.2g.) was then added and the resulting mixture stirred and refluxed for 90minutes. The mixture was filtered, and the filtrate washed with aqueous2N sodium carbonate and with water. After drying over magnesium sulphateand evaporation of the solvent in vacuo, the residue was distilled, inthe presence of a few crystals of potassium acetate, at 132-168 C./ 0.25mm. Hg, to give crude 2-(3-acetoxyoctyl)cyclopent-2- enone. This wasredistilled, with potassium acetate, at 116-135 C./0.15 mm. Hg to give2-(3-acetoxyoctyl)cyclopent-2-enone (28.7 g.), n =1.470.

(g) Preparation of 2-(3-acetoxy0ctyl)-3-cyanocyclopentanone2-(3-Acetoxyoctyl)cyclopent-2-enone (42.8 g.) [prepared as described in(f) above], acetone cyanohydrin (17.0 g.), aqueous sodium carbonatesolution (6.6% w./v.; 18.3 ml.) and methanol (100 ml.) were stirred andrefluxed for 4 hours. Methanol was removed in vacuo, water (100 ml.)added and the mixture extracted with ether and the ether extract driedwith magnesium sulphate. The solvent was removed in vacuo and theresidue distilled at 172-183 C./0.l5 mm. Hg to give2-(3-acetoxyoctyl)-3-cyanocyclopentanone (22.0 g.), n =l.465.

(h) Preparation of 3-hydroxy-2-(3-hydroxyoctyl) cyclopentanecarbonitrile To a stirred solution of2-(3-acetoxyoctyl)-3-cyanocyclopentanone (22 g.) [prepared as describedin (g) above] in methanol (120 ml.) was added dropwise, during minutes,a solution of sodium borohydride (9.2 g.) in 0.2N aqueous sodiumhydroxide solution (60 ml.) at -30 C. The solution was slowly heated toC. and stirred at this temperature for 6 hours. Methanol was removed invacuo, water (100 ml.) added and the mixture extracted with chloroformand dried with magnesium sulphate. The solvent was removed in vacuo andthe residue distilled at 167170 C./0.2 mm. Hg to give 3-hydroxy-2-(3hydroxyoctyl)cyclopentane carbonitrile (15.3 g.), n =1.479.

(i) Preparation of 3-(2-tetrahydropyranyloxy)-2-[3-(2-tetrahydropyranyloxy)octyl] cyclopentane carbonitrile Dihydropyran (29.4g.) was added dropwise at 40 C., with stirring, to3-hydroxy-2-(3-hydroxyoctyl)-cyclopentane carbonitrile (28.0 g.)[prepared as described in (h) above] and concentrated hydrochloric acid(6 drops) in dichloromethane (5 ml.). The temperature was allowed torise to C., maintained at this temperature for minutes and then cooled.Diethyl ether ml.) was added and the solution washed with aqueous 2Nsodium hydroxide and with water and dried over magnesium sulphate. Thesolvent was removed in vacuo to give crude 3-(2tetrahydropyranyloxy)-2-[3-(2 tetrahydropyranyloxy)octyl]cyclopentanecarbonitrile (48.5 g.) which was used as starting material in thefollowing preparation (j) of 3- Z-tetrahydropyranyloxy) -2- 3-Z-tetrahydropyranyloxy)octyl]cyclopentane carbaldehyde without furtherpurification.

(j) Preparation of 3-(Z-tetrahydropyranyloxy)-2-[3-(2-tetrahydropyranyloxy)octyl] cyclopentane carbaldehyde To a vigorouslystirred solution of crude 3-(2-tetrahy dropyranyloxy)-2-[3(Z-tetrahydropyranyloxy) octyl] cyclopentane carbonitrile (48.5 g.)[prepared as described in (i) above] in dry diethyl ether (225 ml.) wasadded a solution of di-isobutylaluminium hydride (22.7 g.) in drybenzene (90 ml.) at 3-7" C. The mixture was stirred at room temperaturefor 15 minutes and then added with stirring to 2N aqueous acetic acid(225 ml.) at less than 15 C. The organic phase was separated, and theaqueous layer extracted with diethyl ether. The combined organic phaseswere washed with aqueous sodium bicarbonate and with water, dried withmagnesium sulphate, and the solvents removed in vacuo. The residue wasdistilled, in the 13 presence of a few crystals of potassium acetate, at175- 214 C./0.15 mm. Hg to give 3-(2-tetrahydropyranyloxy)-2[3-2-tetrahydropyranyloxy)octyl] cyclopentane carbaldehyde (35.2 g.), 111.479.

(k) Preparation of ethyl 7-{3-(2-tetrahydropyranyloxy)- 2 [3 (2tetrahydropyranyloxy)octyl] cyclopentyl}- hepta-1,3,5-trienoate To asolution of -ethoxycarbonylpenta-2,4-dienyltriphenylphosphorane[prepared by adding N aqueous sodium hydroxide (50 ml.) to a stirredsolution of 5-ethoxycarbonylpenta-2,4 dienyltriphenylphosphonium bromide(19.24 g.) in water (1250 ml.) at 1-3" C., extracting with chloroformand concentratnig the extract to about 300 mL] at 2 C, under nitrogen,was added 3-(2-tetrahydropyranyloxy)-2 [3-(Z-tetrahydropyranyloxy)octyl]cyclopentane carbaldehyde (10.25 g.) [prepared as described in (i)above] in chloroform ml.). The solution was allowed to stand at roomtemperature for 18 hours, the chloroform removed in vacuo and theresidue extracted three times with hot petrol (b.p. 40-60 C.). Thecombined petrol extracts were cooled and filtered to remove precipitatedtriphenylphosphine oxide. The filtrate was evaporated in vacuo and theresidue chromatographed on silica gel. Elution with petrol (b.p. 4060C.) gave ethyl 7-{3(Z-tetrahydropyranyloxy)-2-[3-(2-tetrahydropyranyloxy)octyl]cyclopentyl}hepta 1,3,5 trienoate (8.5 g.), x 306 ma, 6 23,800(ethanol); p 1700 cmf 1610 cm? (liquid film).

5-Ethoxycarbonylpenta-2,4 dienyltriphenylphosphoniurn bromide, used as astarting material was prepared as follows:

To a stirred solution of triphenylphosphine (34 g.) in dry benzene (300ml.) was added ethyl 6-bromohexa-2, 4-dienoate g.). After 18 hours, thebenzene was decanted from the precipitated paste which solidified onadding iethyl ether and was ground up and filtered to give5-ethoxycarbonylpenta-2,4 dienyltriphenylphosphonium bromide g.), m.p.139144 C.

(1) Preparation of ethyl 7-{3-(Z-tetrahydropyranyloxy)-- 2-[3-(2tetrahydropyranyloxy) octyl] cyclopentyl}-heptanoate Ethyl7-{3-(Z-tetrahydropyranyloxy)-2-[3-(2tetrahydropyranyloxy)octyl]cyclopentyl} hepta 1,3,5-trienoate (8.5 g.)[prepared as described in (k) above] was dis solved in ethanol (150 ml.)and catalytically hydrogenated using 5% palladium on charcoal withhydrogen pressure of 15 kg./cm. at room temperature. The catalyst wasfiltered off and the ethanol removed in vacuo to give ethyl7-{3-(Z-tetrahydropyranyloxy)-2-[3-(2tetrahydropyranyloxy)octyl]cyclopentyl}heptanoate (7.2 g.), 1.473, whichwas used as starting material in the following preparation (m) of ethyl7-[3-hydroxy-2-(3-hydroxyoctyl)cyclopentyl1heptanoate without furtherpurification.

(m) Preparation of ethyl 7-[3-hydroxy-2-(3-hydroxyoctyl)cyclopentyl1heptanoate A mixture of ethyl7-{3-(2-tetrahydropyranyloxy-Z-[3-(Z-tetrahydropyranyloxy)octyl]cyclopentyl} heptanoate (8.0 g.) [preparedas described in (1) above], ethanol (100 ml.), N HCl (200 ml.) and acation-exchange resin [Dowex resin AGW-X8 H+] (15 g.) was stirred at50-60 C. for 24 hours. The mixture was then cooled and filtered and thesolid washed with diethyl ether and water. Combined filtrate andwashings were evaporated in vacuo to remove organic solvents and theaqueous residue extracted with diethyl ether and dried over anhydroussodium carbonate. The ether was removed in vacuo to give ethyl7-[3-hydroxy-2 (3-hydroxyoctyl) cyclopentyl] heptanoate (4.8 g.) whichwas used as starting material in the following preparation (11) of7-[3-hydroxy-2-(3- hydroxyoctyl)cyclopentyl1heptanoic acid withoutfurther purification.

14 (n) Preparation of 7-[3-hydroxy-2-(3-hydroxyoctyl)-cyclopentyl]heptanoic acid Crude ethyl7-[3-hydroxy-2-(3-hydroxyoctyl)-cyclopentyl]heptanoate (4.8 g.),[prepared as described in (m) above], ethanol (50 ml.) and 2N aqueoussodium hydroxide (50 ml.) were refluxed together for 18 hours. Theethanol was removed in vacuo, water (50 ml.) was added and the causticresidue extracted with diethyl ether. The aqueous phase was acidified topH 1 by the dropwise addition of 2N hydrochloric acid and was thenextracted with diethyl ether, and the ether extract dried over magnesiumsulphate. Evaporation of the ether in vacuo gave 7-[3-hydroxy-2-(3hydroxyoctyl) cyclopentyl1heptanoic acid (3.4 g.) as a mixture ofstereoisomers which were purified and partially separated by preparativethin-layer chromatography on silica gel (HF 254-366), using a 65:15:1v./v. mixture of benzene, dioxan and acetic acid as eluent. Appropriateportions of the adsorbent were removed from the supporting glass plateand extracted with diethyl ether using a Soxhlet apparatus. Evaporationto dryness of the ether extract of the portion farther from the solventfront gave 7-[3-hydroxy-2-(3 hydroxyoctyl)cyclopentyl1heptanoic acid(1.4 g.) [stereoisomer (a), thought to be the stereoisomer where therelative configuration of the hydroxy group on the ring is trans to the3-hydroxyoctyl side chain] which had the following spectroscopicproperties:

v 1700 ClTL (liquid film), N.M.R. (approximately 10% solution indeuterochloroform) 0.896 (triplet I 4 /2 c./s., terminal CH 1.386(singlet, chain CH 1.4-28 (multiplets), 2.366 (triplet I 5 /2 c./s., CHCO), 3.58 and 3.855 (multiplets), 5.55 (3H OH and COOH). Evaporation todryness of the ether extract of the portion nearer to the solvent frontgave a mixture (b) (0.8 g.) containing both possible stereoisomers, cisand trans, which had an additional N.M.R. band at 4.26 (multiplet).

EXAMPLE 2 (a) Preparation of 3-hydroxy-2-(3-hydroxyoctyl) cyclopentanecarbaldehyde To a vigorously stirred solution of 2-(3-acetoxyoctyl)-3-cyanocyclopentanone (2.8 g.) [prepared as described in Example 1 (g)above] in dry diethyl ether ml.) was added a solution ofdi-isobutylaluminium hydride (8.5 g.) in dry benzene (30 ml.) at 48 C.The mixture was stirred at room temperature for 15 minutes and thenadded with stirring to 2N aqueous acetic acid (60 ml.) at 0-15 C. Theorganic phase was separated off, and the aqueous layer extracted withdiethyl ether. The combined organic phases were washed with aqueoussodium bicarbonate and then with water, dried with magnesium sulphate,and the solvents removed in vacuo to give3-hydroxy-2-(3-hydroxyoctyl)cyclopentane carbaldehyde (2.3 g.).

Elemental analysis.Found: C, 69.4; H, 10.8%; C H O requires C, 69.4; H,10.8%. v 1710 cm.- (liquid film).

(b) Preparation of ethyl 7-[3-hydroxy-2(3-hydroxyoctyl)cyclopentyl]hepta-1,3,S-trienoate To a solution ofS-ethoxycarbonylpenta-2,4-dienyltriphenylphosphorane [prepared asdescribed in Example 1(k) above] in chloroform (300 ml.) at 3 C., undernitrogen, was added 3-hydroxy-2-(3-hydroxyoctyl)cyclopentanecarbaldehyde (7.26 g.) [prepared as described in (a) above] inchloroform (25 ml.). The solution was allowed to stand at roomtemperature for 18 hours, the chloroform removed in vacuo and theresidue chromatographed on silica gel. Elution with diethyl ether gaveethyl 7-[3- hydroxy-2-(3-hydroxyoctyl)cyclopentyl1hepta 1,3,5 trienoate(6.5 g.), 11 1710 cm.- 1620 cm.- (liquid film), which was used asstarting material in the following preparation of ethyl7-[3-hydroxy-2-(3-hydroxyoctyl) cyclopentyl]heptanoate without furtherpurification.

(c) Preparation of ethyl7-[3-hydroxy-2-(3-hydroxyoctyl)cyclopenty1]heptanoate Ethyl 7-[3-hydroxy2 (3 hydroxyoctyl)cyclopentyl] hepta-1,3,5-trienoate (4.0 g.) [preparedas described in (b) above] was dissolved in ethanol (100 ml.) andcatalytically hydrogenated using 5% palladium. on charcoal with ahydrogen pressure of kg./cm. at room temperature. The catalyst wasfiltered off and the ethanol removed from the filtrate in vacuo and theresulting residue chromatographed on silica gel. Elution with diethylether gave ethyl 7-[3-hydroxy-2-(3-hydroxyoctyl)cyclopentyl] heptanoate(1.8 g.).

Elemental analysis.Found: C, 70.9; H, 11.1% C H O requires C, 71.3; H,11.4%. 11 1720 cm.- (liquid film).

EXAMPLE 3 (a) Preparation of 1,4-dioxa-6-(3-acetoxyoctyl)-7- cyano spiro[4,4] nonane A mixture of 2-(3-acetoxyoetyl)-3-cyanoeyclopentanone (27.9g.) [prepared as described in Example 1 (g.) above], ethylene glycol(7.5 g.) and p-toluene sulphonic acid (1.0 g.) in benzene (300 ml.) washeated under reflux for 2 /2 hours, and the water liberated wascontinuously removed by means of a Dean and Stark head. An excess ofsodium carbonate was added to the solution, which was shaken, and thenfiltered. The solvent was removed from the filtrate in vacuo and theresulting residue was distilled under reduced pressure, in the presenceof a few crystals of potassium acetate, to give 1,4-dioxa-6-(3-acetoxyoctyl)-7-cyanospiro[4,4]nonane (23.7 g.), b.p. 157-169" C./0.1mm. Hg.

Elemental analysis-Found: C, 67.2; H, 9.1; N, 3.9%; C H NO requires C,66.9; H, 9.0; N, 4.3%. v 2250 cm.- 1730 cm.- 1250 cm? (liquid film).

(b) Preparation of l,4-dioxa-7-formyl-6-(3-hydroxyoctyl) spiro [4,4]nonane To a vigorously stirred solution of1,4-dioxa-6-(3-acetoxyoctyl)-7-cyanospiro[4,4]nonane (8.08 g.) [preparedas described in (a) above] in dry diethyl ether (100 ml.) was added asolution of di-isobutylaluminium hydride (14.2 g.) in dry benzene (50ml.) at 411 C. The mixture was stirred at room temperature for 10minutes and then added with stirring to 2N aqueous acetic acid (100 ml.)at 0-20" C. The organic phase was separated OE, and the aqueous layerextracted with diethyl ether. The combined organic phases were washedwith an aqueous solution of sodium bicarbonate and then with water,dried with magnesium sulphate, and the solvents removed in vacuo to give1,4-dioXa-7-formyl-6-(3-hydroxyoctyl) spiro[4,4]nonane (6.7 g.), v 1710cm.- (liquid film), which was used as starting material in the followingpreparation (c) of 1,4-dioxa-l-(6-ethoxycarbonylhexa-1,3,5-trienyl)-6-(3-hydroxyoctyl)spiro[4,4]nonane without furtherpurification.

(0) Preparation of 1,4-dioxa-7- 6ethoxycarbonylhexa- 1,3,5-trienyl) -6-3-hydroxyoctyl) spiro [4,4] nonane To a solution of5-ethoxycarbonylpenta-2,4-dienyltriphenylphosphorane [prepared asdescribed in Example 1 (k) above] in chloroform (300 ml.) at 2 C., undernitrogen, was added 1,4-dioxa7-formyl6-(3-hydroxyoctyl) spiro[4,4]nonane(6.0 g.) [prepared as described in (b) above] in chloroform ml.). Thesolution was allowed to stand at room temperature for 18 hours, thechloroform was removed in vacuo and the residue extracted twice with hotpetroleum ether (b.p. 60 0.). The combined extracts were cooled andfiltered, the filtrate was evaporated in vacuo and the resulting residuechromatographed on silica gel. Elution with diethyl ether gave 1,4-dioxa-7-(6-ethoxycarbonylhexa-1,3,5-trienyl)-6 (3 hy- 16droxyoctyl)spiro[4,4]nonane (4.8 g.), k 305 m 6 34,200 (ethanol); 111700 cm.- 1610 cm.- (liquid film).

(d) Preparation of 1,4-dioxa-7-(6-ethoxycarbonylhexyl)- 6-3-hydroxyoctyl) spiro [4,4] nonane 1,4 Dioxa 7 (6 ethoxycarbonylhexa1,3,5-trienyl) 6 (3 hydroxyoctyl)spiro[4,41 nonane. (4.8 g.) [preparedas described in (c) above] was dissolved in ethanol (100 ml.) andcatalytically hydrogenated using 5% palladium charcoal with a hydrogenpressure of 15 kg./cm.' at room temperature. The catalyst was filteredoff and the ethanol removed from the filtrate in vacuo to give impure1,4-dioxa-7-(6-ethoxycarbonylhexyl)-6-(3 hydroxyoctyl)spiro[4,4]nonane(4.4 g.) v 3450 cmf 1725 cm. (liquid film). This was used as startingmaterial in the following preparation (e) of 1,4-dioxa-7-(6-carboxyhexyl) 6 (3 hydroxyoctyl)spiro[4,4]nonane without furtherpurification.

(e) Preparation of 1,4-dioxa 7 (6 carboxyhexyl)-6-(3- hydroxyoctyl)spiro [4,4] nonane A mixture of 1,4-dioxa 7 (6-ethoxycarbonylhexyl)-6-(3-hydroxyoctyl)spiro[4,4]nonane (2.4 g.) [prepared as described in (d)above], ethanol (25 ml.) and 2N aqueous sodium hydroxide solution (25ml.) was heated to reflux for 16 hours. The ethanol was removed invacuo, the mixture was treated with water (50 ml.) and then extractedwith diethyl ether. The aqueous phase was acidified to pH 1 by thedropwise addition of concentrated hydrochloric acid and then extractedwith diethyl ether. The ether extract was dried over magnesium sulphate.Evaporation of the ether in vacuo gave 1,4-dioXa-7-(6-carboxyhexyl)-6(3-hydroxyoctyl) spiro [4,4] nonane (1.5 g.)

Elemental analysis.Found: C, 68.4; H, 10.2%;

22 40 5 requires C, 68.7; H, 10.5% 11 1705 cmr 1040 cmf 950 cm? (liquidfilm).

(f) Preparation of 7-[2-(3-hydroxyoctyl)-3-oXocyclopentyl]heptanoic acid1,4-Dioxa 7 (6-carboxyhexyl) 6 (3-hydroxyoctyl) spiro[4,4]nonane (1.4g.) [prepared as described in (e) above] was dissolved in an aqueousacetic acid solution (30 ml.) and left to stand at room temperature forthree days. Water (150 ml.) was then added to the solution which wasthen extracted twice with diethyl ether. The combined ethereal extractswere washed three times with water, dried with magnesium sulphate andfiltered. The filtrate was evaporated in vacuo at or below 55 C., thelast traces of acetic acid being removed by the addition of smallquantities of benzene to the residue and evaporating again in vacuo togive 7-[2-(3-hydroxyoctyl)-3- oxocyclopentyl1heptanoic acid (0.92 g.).

Elemental analysis.-Found: C, 70.6; H, 10.3%;

zo 2e 4. requires C, 70.5; H, 10.7%.

NMR (10% deuterochloroform solution): 0.906 (triplet J=5 c./s., CH 1.366(broad singlet, chain CH l.41.96 (multiplets), 2.236 and 2.356 (twooverlapping triplets 1:6.5 c./s., CH CO and CHCO), 3.606 (multiplet),6.86 (OH, COOH).

EXAMPLE 4 Preparation of methyl 7-[3-hydroXy-2-(3-hydroxyoctyl)-cyclopentyl]heptanoate, (mixture of cisand trans-isomers) A solution ofdiazomethane (2.5 g.) in dry diethyl ether ml.) was added to a solutionof 7-[3-hydroxy-2-(3- hydroxyoctyl) cyclopentyl]heptanoic acid (3.4 g.)[mixture (b) of cisand trans-isomers, prepared as described in Example1(n)] in dry diethyl ether (25 ml.). The resulting solution was allowedto stand at ambient temperature for 18 hours, during which time a solidprecipitated. The solid removed by filtration and the filtrateevaporated 1 7 in vacuo to give methyl 7-[3=hydroxy-2-(3-hydroxyocty1)cyclopentyl]heptanoate (3.1 g.), a mixture of the cisand trans-isomers.

Elemental analysis.-Found: C, 70.4; H, 11.0%;

21 4o 4 requires C, 70.7; H, 11.3%.

u 1730 cm. (liquid film).

EXAMPLE Preparation of methyl 71[3-hydroxy-2-(3-hydroxyoctyl)-cyclopentyl1heptanoate (trans-isomer) 7-[3-hydroxy 2(3-hydroxyoctyl)cyclopentyl]heptanoic acid (0.3 g.) [stereoisomer (a),prepared as described in 1(n)] was dissolved in dry diethyl ether (2.5ml.) at ambient temperature and treated with a solution of diazomethane(0.32 g.) in dry diethyl ether ml.) and the resultingtsolution wasallowed to stand at ambient temperature for 12 hours. The mixture wasthen filtered and the filtrate evaporated in vacuo to give methyl7-[3-hydroxy-2-(3-hydroxyoctyl)cyclopentyl]heptanoate (0.3 g.) [thoughtto be the stereoisomer where the relative configuration of the hydroxygroup on the ring is trans to the 3-hydroxyoctyl side chain].

Elemental analysis.-Found: C, 70.6; H, 11.3%;

requires C, 70.7; H, 11.3%.

11 1730 cm.- (liquid film).

EXAMPLE 6 Preparation of 7- 3-acetoxy-2- 3-acetoxyoctylcyclopentyl]heptanoic acid To a solution of7-[3-hydroxy-2-(3-hydroxyoctyl)cyclopentyl]heptanoic acid (0.34 g.)[mixture (b) of cisand trans-isomers, prepared as described in Examplel(n)] in dry pyridine 10 ml.) was added acetic anhydride (10 ml.). Theresulting solution was allowed to stand at ambient temperature for 3days, and then diluted with water while cooling externally with an icebath. The resulting aqueous solution was extracted twice with diethylether and the combined extracts washed with dilute hydrochloric acid andwater, then dried over magnesium sulphate. Evaporation in vacuo gave7-[3-acetoxy-2-(3-acetoxy0ctyl)cyclopentyl]heptanoic acid (0.36 g.).

Elemental analysis.Found: C, 68.0; H, 9.7%;

requires C, 67.6; H, 9.9%.

vmax, 1725 GEL-1, 1700 cm." 1245 cm.- (liquid film).

EXAMPLE 7 Preparation of methyl 7-[3-methoxy-2-(3-methoxyoctyl)-cyclopentyl1heptanoate A solution of methyl7-[3-hydroxy-2-(Ii-hydroxyoctyl) cyclopentyl]heptanoate (0.82 g.)[mixture of cisand trans-isomers, prepared as described in Example 4)]in dry ether ml.) was cooled to 40 C. and treated with boron trifiuoridedimethyl etherate (0.5 ml.), immediately followed by a portion offreshly prepared dry diazomethane in diethyl ether, cooled to 40 C.Further diazomethane solution was then added until a yellow colourpersisted. After standing at -40 C. for 15 minutes and at ambienttemperature overnight, the mixture was filtered and the filtrate waswashed with an aqueous sodium bicarbonate solution and water, dried overmagnesium sulphate and evaporated in vacuo to give impure methyl7-[3-methoxy 2 (3-methoxyoctyl)cyclopentyl] heptanoate (0.73 g.). Thiswas purified by preparative thin-layer chromatography on silica gel(HF254-366) using a 65: 15:1 v./v. mixture of benzene, dioxan and aceticacid as eluent. The appropriate portion of the adsorbent was removedfrom the supporting glass plate and extracted with diethyl ether bymeans of a Soxhlet apparatus. Evaporation of the resulting ether extractgave methyl 7- 18 [3-methoxy 2 (3-methoxyoctyl)cyclopentyl]heptanoate(0.18 g.).

Elemental analysis.Found: C, 71.7; H, 11.2%;

requires C, 71.8; H, 11.5%.

11 1730 cmf 1100 cm.- (liquid film).

EXAMPLE 8 Preparation of N-methyl-7-[3 hydroxy-2-(3-hydroxyoctylcyclopentyl] heptanamide To a solution of methyl7-[3-hydroxy-2-(3-hydroxyoctyl)cyclopentyl]heptanoate (0.27 g.) [mixtureof cisand trans-isomers, prepared as described in Example 4] in ethanol(4 ml.) was added 33% methylamine in ethanol (1 ml.) followed by sodiumethoxide in ethanol [0.2 ml. of a solution prepared by dissolving sodium(0.1 g.) in ethanol (2 ml.)]. The resulting solution was heated toreflux for 9 hours and the ethanol removed in vacuo. The residue wasdiluted with ice-cooled water, extracted with benzene, and the extractwashed with water and dried over magnesium sulphate and evaporated invacuo. The resulting residue was washed with hot diethyl ether to giveN-methyl-7-[3-hydroxy 2 (3-hydroxyoctyl)cyclopentyl] heptanamide (0.02g.).

Elemental analysis.--Found: C, 71.5; H, 11.3; N, 3.4%; C H NO requiresC, 70.9; H, 11.6; N, 3.9%.

u 1650 cmr' 1560 cm." (liquid film).

EXAMPLE 9 Preparation of7-[3-hydroxy-2-(3-hydroxyoctyl)cyclopentyl1heptauohydrazide A solutionof methyl 7-[3-hydroxy-2-(3-hydroxyoctyl) cyclopentyl1heptanoate (0.3g.) (the stereoisomer thought to have the trans-configuration, preparedas described in Example 5) and hydrazine hydrate (0.5 g.) in methanol(10 ml.) was refluxed for 30 hours. The methanol was removed in vacuoand the residue diluted with water, the resulting solution extractedtwice with diethyl ether, and the combined ethereal extracts were driedover magnesium sulphate. Evaporation in vacuo gave a glassy solid whichcrystallised from diethyl ether to give 7- [3-hydroxy-2-( 3hydroxyoctyl)cyclopentyl1heptanohyhydrazide (0.15 g.) [thought to be thestereisomer where the relative configuration of the hydroxy group on thering is trans to the 3-hydroxyoctyl side-chain], m.p. 81-83 C.

Elemental analysis.Found: C, 67.5; H, 11.3; N, 7.7%; C H O N requires C,67.4; H, 11.3; N, 7.9%.

u 1640 cmf 1610 cmr 1535 cm.- (KBr disc.).

The present invention includes within its scope pharmaceuticalcompositions which comprise one or more compounds of general formula I,or non-toxic salts thereof, together with a pharmaceutical carrier orcoating. 'In clinical practice the compounds of the present inventionwill normally be administered orally, rectally or parenterally.

Solid compositions for oral administration include compressed tablets,pills, dispersible powders and granules. In such solid compositions oneor more of the active compounds is, or are, admixed with at least oneinert diluent such as calcium carbonate, potato starch, alginic acid, orlactose. The compositions may also comprise, as is normal practice,additional substances other than inert diluents, e.g. lubricatingagents, such as magnesium stearate. Liquid compositions for oraladministration include pharmaceutically acceptable emulsions, solutions,suspen sions, syrups and elixirs containing inert diluents commonly usedin the art, such as water and liquid paraffin. Besides inert diluentssuch compositions may also comprise adjuvants, such as wetting andsuspending agents, and sweetening, fiavouring, perfuming and preservingagents. The compositions according to the invention, for oraladministration, also include capsules of absorbable material such asgelatin containing one or more of the active substances with or withoutthe addition of diluents or excipients.

Solid compositions for rectal administration includes suppositoriesformulated in known manner and contaln ing one or more of the activecompounds.

Preparations according to the invention for parenteral administrationinclude sterile aqueous or non-aqueous solutions, suspensions, oremulsions. Examples of nonaqueous solvents or suspending media arepropylene glycol, polyethylene glycol, vegetable oils such as olive oil,and injectable organic esters such as ethyl oleate. These compositionsmay also contain adjuvants such as preserving, wetting, emulsifying anddispersing agents. They may be sterilised, for example, by filtrationthrough a bacteriaretaining filter, by incorporation of sterilisingagents in the compositions, by irradiation, or by heating. They may alsobe manufactured in the form of sterile solid compositions, which can bedissolved in sterile water or some other sterile injectable mediumimmediately before use.

The percentage of active ingredient in the compositions of the inventionmay be varied, it being necessary that it should constitute a proportionsuch that a suitable dosage for the therapeutic effect desired shall beobtained. Obviously several unit dosage forms may be administered atabout the same time. In general, the preparations should normallycontain at least 0.025% by weight of active substance when required foradministration by injection; for oral administration the preparationswill normally contain at least 0.1% by weight of active substance.

In human therapy for the treatment of hypertension the compositionsshould generally be administered so as to give, in the case ofintravenous infusion, between 0.3 and 9.0 mg. of active substance perkilogramme body weight per day, preferably in three periods per day.

In human therapy for the inhibition of gastric acid secre tion thecompositions should generally be administered so as to give, in the caseof oral administration, between 2.0 and 40 mg. of active substance perkilogramme body weight per day in divided doses.

The following Example illustrates pharmaceutical compositions accordingto the invention:

EXAMPLE 10 7- [3-Hydroxy-2- 3-hydroxyoctyl) cyclopentyl] heptanoic acid(300 mg., mixture of cisand trans-isomers) was dissolved in ethanol (1ml.) and the solution obtained was added to an aqueous solution ofsodium carbonate (50 mg. in 12 ml.). Aqueous sodium chloride solution (2ml., 0.9% w./v.) was then added to give a final volume of 15 ml. Thesolution was then sterilised by passage through a bacteria-retainingfilter and placed in 1.5 ml. portions in, ml. ampoules, to give 3 mg. ofthe heptanoic acid derivative (in the form of its sodium salt) perampoule. The contents of the ampoules were freeze-dried and the am-'poules sealed. Dissolution of the contents of an ampoule in a suitablevolume, e.g. 2 ml., of sterile water or physiological saline gave asolution ready for administration by injection.

We claim:

1. A cyclopentane of the formula:

--(CHz)mCOR wherein A is carbonyl or -CH(OR R is alkyl of 1 throughcarbon atoms, cycloalkyl of 3 through 10 carbon atoms, or alkyl of 1through 4 carbon atoms substituted by cycloalkyl of 3 through 10 carbonatoms, m is 4 or 6, R is hydroxy or OR wherein R is alkyl of 1 through 4carbon atoms, and R is hydrogen, alkyl of 1 through 4 carbon atoms, oralkanoyl of formula wherein R is alkyl of 1 through 4 carbon atoms, and,when A is CH('OR the symbols R are the same,

and, when R is hydroxy, pharmaceutically acceptable nontoxic saltsthereof.

2. A cyclopentane according to Claim 1 of the formula:

, ormmcon wherein R is alkyl of 1 through 10 carbon atoms, cycloalkyl of3 through 10 carbon atoms, or alkyl of 1 through 4 carbon atomssubstituted by cycloalkyl of 3 through 10 carbon atoms, m is 4 or 6, Ris hydroxy or OR wherein R is alkyl of 1 through 4 carbon atoms, and Ris hydrogen, alkyl of 1 through 4 carbon atoms or alkanoyl of formula COR wherein R9 is alkyl of 1 through 4 carbon atoms, and the symbols R arethe same and, when R is hydroxy, pharmaceutically acceptable non-toxicsalts thereof.

3. A cyclopentane according to claim 2 in which R is alkyl of 5 carbonatoms.

4. A cyclopentane according to claim 2 in which R is n-pentyl, m is 6, Ris hydroxy, methoxy or ethoxy, and R is hydrogen, methyl or acetyl, and,when R is hydroxy, pharmaceutically acceptable non-toxic salts thereof.

5. The cyclopentane according to claim 2 which is 7- [3-hydroxy-2 (3hydroxyoctyl)cyclopentyl]heptanoic acid, and alkyl esters with 1 through4 carbon atoms in the alkyl group and pharmaceutically acceptablenontoxic salts thereof.

6. The cyclopentane according to claim 2 which is methyl 7-[3-hydroxy-2(3 hydroxyoctyl)cyclopentyl] heptanoate.

7. The cyclopentane according to claim 2 which is ethyl 7- [3-hydroxy-2-(3-hydroxyoctyl) cyclopentyl1heptanoate.

8. The cyclopentane according to claim 2 which is 7-[3- acetoxy-2-(3acetoxyoctyl)cyclopentyl]heptanoic acid, and alkyl esters with 1 through4 carbon atoms in the alkyl group and pharmaceutically acceptablenon-toxic salts thereof.

9. The cyclopentane according to claim 2 which is methyl 7-[3-methoxy-2(3 methoxyoctyl)cyclopentyl] heptanonate.

10. The cyclopentane according to claim 2 which is the 11,12 transsteroisomer of 7-[3-hydroxy-2-(3-hydroxyoctyl(cyclopentyl]heptanoic acidwhich has the following spectroscopic properties: 1 1700 cm. (liquidfilm), N.M.R. (approximately 10% solution in deuterochloroform) 0.896(triplet J=4 /z c./s., terminal CH 1.385 (singlet, chain CH 1.4-26(multiplets), 2.326 (triplet J=5 /2 c./s., CH CO), 3.58 and 3.856 (multiplets), 5.55 (3H=OH and COOH).

11. The cyclopentane according to claim 10 in association with its11,12-cis stereoisomer.

12. A cyclopentane according to claim 1 of the forwherein R is alkyl of1 through 10 carbon atoms, cycloaklyl of 3 through 10 carbon atoms, oralkyl of 1 through 4 carbon atoms substituted by cycloalkyl of 3 through10 carbon atoms, In is 4 or 6, R is hydroxy or O:R wherein R is alkyl of1 through 4 carbon atoms, and R is hydrogen, alkyl of 1 through 4 carbonatoms or alkanoyl of formula --COR9 wherein R is alkyl of 1 through 4carbon atoms, and when R is hydroxy, pharmaceutically acceptablenon-toxic salts thereof.

13. A cyclopentane according to claim 12 in which R is alkyl of 5 carbonatoms.

21 22 14. A cyclopentane according to claim 12 in which R ReferencesCited is n-pentyl, m is 6, R is hydroxy, methoxy or ethoxy and ATE P Ris hydrogen, methyl or acetyl and, when R is hydroxy, UNITED T S AT}: Spharmaceutically acceptable non-toxic salts thereof. 3,678,092 7/1972Fmch 260468 D 15. The cyclopentane according to claim 10 which is7-[2-(3-hydroxyoctyl)-3-oxocyc1openty1]heptanoic acid, 5 ROBERT GERSTLPnmary Exammer and alkyl esters with 1 through 4 carbon atoms in thealkyl U S Cl X R group and pharmaceutically acceptable non-toxic salts260 2472 R 268 R thereof. a

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,845,096 Dated October 29, 1974 Inventor(s) MICHAEL PETER LEAR CATON eta1 It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Col. 1, line 3, change "Arevor" to Trevor and Col. 1, line 4, change"Fomford" to Romford'--.

"led and sealed this 1st day 02. April 1975.

ra-r1 Lulu-.1 311112951:

C. IZARSIEALL DAM? RUTI'L C iZA OI- C I I ommlsstoner o1. ratents andTrademarks attesting Officer USCOMM-DC 603 6-969 u.s. covnuunn PRINTINGomc: nu o-au-ssa.

FO RM PO-1050 (10-69)

1. A CYCLOPENTANE OF THE FORMULA: